Related Experiment Videos
Tonic dopamine inhibition of L-type Ca2+ channel activity reduces alpha1D Ca2+ channel gene expression
D M Fass1, K Takimoto, R E Mains
1Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Abstract:
Hormones and neurotransmitters have both short-term and long-term modulatory effects on the activity of voltage-gated Ca2+ channels. Although much is known about the signal transduction underlying short-term modulation, there is far less information on mechanisms that produce long-term effects. Here, the molecular basis of long-lasting suppression of Ca2+ channel current in pituitary melanotropes by chronic dopamine exposure is examined. Experiments involving in vivo and in vitro treatments with the dopaminergic drugs haloperidol, bromocriptine, and quinpirole show that D2 receptors persistently decrease alpha1D L-type Ca2+ channel mRNA and L-type Ca2+ channel current without altering channel gating properties. In contrast, another L-channel (alpha1C) mRNA and P/Q-channel (alpha1A) mRNA are unaffected. The downregulation of alpha1D mRNA does not require decreases in cAMP levels or P/Q-channel activity. However, it is mimicked and occluded by inhibition of L-type channels. Thus, interruption of the positive feedback between L-type Ca2+ channel activity and alpha1D gene expression can account for the long-lasting regulation of L-current produced by chronic activation of D2 dopamine receptors.
Insights
Chronic dopamine exposure persistently reduces L-type calcium channel current in pituitary cells by decreasing alpha1D calcium channel mRNA. This long-lasting effect involves interrupting a positive feedback loop with gene expression.
Area of Science:
- Neuroendocrinology
- Molecular Pharmacology
- Calcium Channel Regulation
Background:
- Hormones and neurotransmitters modulate voltage-gated calcium channels with both short-term and long-term effects.
- Mechanisms underlying long-term modulation of calcium channels remain less understood compared to short-term effects.
Purpose of the Study:
- To investigate the molecular basis for long-lasting suppression of calcium channel current in pituitary melanotropes induced by chronic dopamine exposure.
- To elucidate the role of D2 dopamine receptors in regulating specific calcium channel subtypes.
Main Methods:
- In vivo and in vitro treatments with dopaminergic drugs (haloperidol, bromocriptine, quinpirole).
- Measurement of alpha1D L-type calcium channel mRNA levels.
- Assessment of L-type calcium channel current and gating properties.
Main Results:
- Chronic D2 receptor activation persistently decreased alpha1D L-type calcium channel mRNA and current in pituitary melanotropes.
- Alpha1C L-type and alpha1A P/Q-type calcium channel mRNA levels were unaffected.
- The observed downregulation of alpha1D mRNA was independent of cAMP levels or P/Q-channel activity but was mimicked and occluded by L-type channel inhibition.
Conclusions:
- Long-lasting suppression of L-type calcium channel current by chronic D2 dopamine receptor activation is mediated by a decrease in alpha1D mRNA.
- This regulation results from the interruption of a positive feedback loop between L-type calcium channel activity and alpha1D gene expression.